EP Application No. 90 306 204.0 describes a process for the preparation of imidazole intermediates which comprises a high pressure liquid ammonia condensation of an alkyl alkylimidate with dihydroxyacetone to give 2-alkyl-5hydroxymethylimidazoles. Subsequent N-alkylarylation and oxidation yields 1-alkylaryl-2-alkyl-5-formylimidazoles. Although this process produces the key imidazole intermediates necessary for preparing the angiotensin II receptor antagonizing imidazoles described therein, the high pressure step limits the quantity of compound that can be produced using this method. Therefore, there is a need for an alternate method for the preparation of the imidazole intermediates on a commercial scale.
A further challenge in developing an alternate process is the fact that the regiospecific synthesis of N-substituted imidazoles is not a straight forward operation. Few syntheses exist which result in the exclusive formation of 1,2,5-substitution on the imidazole ring.
It has now been found that the substituted 5-formylimidazole intermediates can be prepared by reacting a 2-halo-2-propenal-3-alkyl ether,-3-alkyl thioether, or -3-amine with a N-( 1-iminoalkyl)aminoalkylaryl compound to produce said intermediates efficiently in high yield and high purity. The efficiency of the process and the quality and yields of the imidazole intermediates are particularly important when preparing compounds on a large scale for therapeutic use.